Genetics, glycemic control and the microbiome in cystic fibrosis

囊性纤维化的遗传学、血糖控制和微生物组

• 批准号: 10669935
• 负责人: Laura N Brenner
• 金额: $ 5.39万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669935
• 关键词: Adult; Affect; Age; Antibiotics; Artificial Pancreas; Beta Cell; Biodiversity; Bionics; Blood Glucose; Body mass index; Carbohydrates; Caring; Cell physiology; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Communities; Complex; Complication; Coupled; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Devices; Diabetes Mellitus; Diagnosis; Disease; Enrollment; Ethnic Origin; Etiology; European; Family; Feces; Funding; Genetic; Genetic Determinism; Glucagon; Glucose; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intake; Intervention; Investigation; Life; Life Expectancy; Linear Regressions; Link; Lung; Lung infections; Measures; Mediating; Mediation; Medical Genetics; Mendelian randomization; Mentors; Methods; Microbe; Microbial Taxonomy; Modeling; Modification; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Outcome; Pancreas; Patients; Pattern; Persons; Pseudomonas aeruginosa; Pulmonary Function Test/Forced Expiratory Volume 1; Quality of life; Randomized; Randomized Clinical Trials; Recording of previous events; Research; Resistance; Risk; Sampling; Serum; Shotguns; Sputum; Staphylococcus aureus; Structure; Surface; System; Techniques; Technology; Testing; Therapeutic; Time; Training; bacterial community; base; biobank; blood glucose regulation; career; clinical predictors; cystic fibrosis patients; cystic fibrosis related diabetes; fecal microbiome; genetic predictors; genetic variant; glucose monitor; glycemic control; gut microbiome; improved; innovation; insight; instrument; lung microbiome; mathematical algorithm; metagenomic sequencing; microbial; microbiome; microbiome alteration; microbiome composition; microbiome research; mortality; novel; patient population; polygenic risk score; pulmonary function; response; trait; treatment as usual; treatment response; trial design

Cystic fibrosis related diabetes (CFRD) is the most common non-pulmonary complication of cystic fibrosis (CF), affecting up to 50% of adults. This diagnosis is linked to more pulmonary exacerbations, worsening lung function, and increased mortality compared to those without CFRD. Individuals with CFRD have more Pseudomonas Aeruginosa and Staphylococcus Aureus pulmonary infections determined by culture based microbial analysis. However, the specific microbiome seen in CFRD and how the microbiome changes with glycemic manipulation is not understood. The development of CFRD may also be influenced by genetic traits for insulin resistance and beta cell function, though studies evaluating this are limited. Insulin is the only recommended treatment that has been shown to improve pulmonary outcomes in CFRD; however, good glycemic control is difficult to achieve in this patient population due to high carbohydrate intake, frequent hypoglycemia, and the added burden of diabetes tasks. Artificial pancreas (AP) technology is a promising approach to controlling blood glucose with greater accuracy and ease than conventional methods. We have funding to study an AP device, the bionic pancreas (BP), in a randomized parallel design clinical trial in subjects with poorly controlled CFRD (R01DK119699-01, PI:Putman). These subjects will be randomized to usual care (UC) or the BP for 6 months, evaluating the impact of the BP not only on glycemic control but also on CF-specific outcomes including nutritional status and pulmonary function. We will leverage this funded trial to investigate novel clinical and genetic predictors of CFRD and will use state-of-the-art microbiome analytic techniques to understand how glycemic control impacts microbiome diversity in CF. Aim 1 will compare the microbiome in CFRD subjects participating in this trial to biorepository samples from non-CFRD subjects and determine how baseline glycemia influences the microbiome. Aim 2 will investigate genetic and clinical predictors of baseline glycemia and response to the BP intervention in subjects with CFRD. Aim 3 will evaluate how strict glycemic control achieved with the BP impacts microbiome diversity over 6 months, and if the change in lung function seen with improved glycemia is mediated through the change in microbiome. In summary, the research and mentoring plan proposed in this K23 application will test innovative hypotheses about glycemic traits and the microbiome in patients with CFRD, will broaden our understanding of CFRD, and will provide the necessary training and investigational niche for Dr. Brenner to develop a successful, independent career in clinical research.

囊性纤维化相关糖尿病（CFRD）是糖尿病最常见的非肺部并发症 囊性纤维化 (CF)，影响高达 50% 的成年人。该诊断与更多肺部疾病有关 与没有症状的患者相比，病情加重，肺功能恶化，死亡率增加 CFRD。患有 CFRD 的个体有更多的铜绿假单胞菌和葡萄球菌 通过基于培养的微生物分析确定金黄色葡萄球菌肺部感染。然而， CFRD 中观察到的特定微生物组以及微生物组如何随血糖变化 操纵不被理解。 CFRD的发生也可能受到遗传因素的影响 胰岛素抵抗和β细胞功能的特征，尽管评估这一点的研究有限。 胰岛素是唯一已被证明可以改善肺功能的推荐治疗方法 CFRD 的结果；然而，该患者很难实现良好的血糖控制 由于高碳水化合物摄入、频繁低血糖以及增加的负担而导致的人群 糖尿病任务。人工胰腺（AP）技术是一种有前途的控制血液的方法 与传统方法相比，测量葡萄糖的准确性和简便性更高。我们有资金去学习 AP 设备，仿生胰腺 (BP)，在受试者中进行的随机平行设计临床试验 CFRD 控制不佳（R01DK119699-01，PI：Putman）。这些受试者将被随机分配 进行常规护理 (UC) 或血压 6 个月，评估血压不仅对血糖的影响 控制，还包括 CF 特定的结果，包括营养状况和肺功能。 我们将利用这项资助的试验来研究 CFRD 的新临床和遗传预测因素 并将使用最先进的微生物组分析技术来了解血糖控制如何 影响 CF 中微生物组的多样性。目标 1 将比较 CFRD 受试者的微生物组 参与这项试验，对来自非 CFRD 受试者的生物储存库样本进行试验，并确定如何 基线血糖影响微生物群。目标 2 将研究遗传和临床 CFRD 受试者基线血糖和血压干预反应的预测因子。目的 3 将评估通过 BP 实现的严格血糖控制如何影响微生物组多样性 超过 6 个月，并且如果随血糖改善而出现的肺功能变化是介导的 通过微生物组的变化。 综上所述，本次K23申请中提出的研究和指导计划将测试 关于 CFRD 患者血糖特征和微生物群的创新假设，将 扩大我们对 CFRD 的理解，并将提供必要的培训和研究 布伦纳博士在临床研究领域发展成功、独立的职业生涯。